Matrix metalloproteinases (MMPs) are a family of at least 15 enzymes that degrade the extracellular matrix (ECM) (Borden and Heller (1997) Crit. Rev. Eukaryotic Gene Expr. 7:159-178). These enzymes have essential roles in modeling and remodeling the ECM in normal physiology and disease pathology. Several of these enzymes have the unique ability to degrade the interstitial collagens (types I, II, and III), the body's most abundant proteins. MMP-1 is the most ubiquitously expressed interstitial collagenase, thereby assigning it a prominent role in collagen degradation.
Overexpression of MMP-1 is associated with several pathological conditions, including the irreversible degradation of cartilage, tendon, and bone in arthritis (Vincenti, et al. (1996) Crit. Rev. Eukaryotic Gene Expr. 6:391-411) and the degradation of collagens I and III in tumor invasion and metastasis (Chambers and Matrisian (1997) J. Nat'l Cancer Inst. 89:1260-1270; Murray, et al. (1996) Nat. Med. 2:461-462). Patients with tumors that express MMP-1 have an overall poorer prognosis than patients with tumors that do not express this protein (Murray, et al. (1996) supra; Murray, et al. (1998) J. Pathol. 185:256-261).
This overexpression of MMP-1 has been suggested to be due to the juxtaposition of transcription factor binding sites within the promoter of this gene and to the cooperativity among the factors that bind these sites (Buttice, et al. (1996) Oncogene 13:2297-2306; Basuyaux, et al. (1997) J. Biol. Chem. 272:26188-26195; Gutman and Waslyk (1990) EMBO J. 9:2241-2246; Benbow and Brinckerhoff (1997) Matrix Biol. 15:519-526).
Most normal cells express modest, but detectable, levels of MMP-1 constitutively, and this expression increases substantially in the presence of cytokines or growth factors (Vincenti, et al. (1996) Crit. Rev. Eukaryotic Gene Expr. 6:391-411; Rutter, et al. (1997) J. Cell Biochem. 66:322-336; Aho, et al. (1997) Eur. J. Biochem. 247:503-510; Delany and Brinckerhoff (1992) J. Cell Biochem. 50:400-410).
A ˜770 nucleotide antisense RNA molecule capable of silencing MMP-1 expression was found to decrease MMP-1 expression in melanoma cells and block in vitro invasion of a collagen matrix (Durko, et al. (1997) Biochim. Biophys. Acta 1356:271-80). Using this same antisense RNA molecule, MMP-1 protein expression and enzyme activity were decreased in chondrosarcoma cells and these cells demonstrated a significant decrease in their ability to invade a collagen I barrier (Jiang, et al. (2003) J. Orthop. Res. 21(6):1063-70).